Several publications and patent documents are cited throughout the specification in order to describe the state of the art to which this invention pertains. Full citations for those references that are numbered can be found at the end of the specification. Each citation is incorporated herein as though set forth in full.
Pancreatic cancer continues to have one of the highest mortality rates of any malignancy. Each year, 28,000 patients are diagnosed with pancreatic cancer, and most will die of the disease. The vast majority of patients are diagnosed at an advanced stage of disease because currently no tumor markers are known that allow reliable screening for pancreas cancer at an earlier, potentially curative stage. This is a particular problem for those patients with a strong familial history of pancreatic cancer, who may have up to a 5-7 fold greater risk of developing pancreatic cancer in their lifetime. Despite several advances in our basic understanding and clinical management of pancreatic cancer, virtually all patients who will be diagnosed with pancreatic cancer will die from this disease. The high mortality of pancreatic cancer is predominantly due to consistent diagnosis at an advanced stage of disease, and a lack of effective screening methods.
Infiltrating ductal adenocarcinoma of the pancreas is one of the most aggressive of all of the solid neoplasms, and invasive pancreatic cancer is often associated with a prominent host desmoplastic response. Besides the potential aggressiveness of neoplastic cells themselves, this host response at the site of primary invasion has been considered an important factor in pancreatic cancer progression. Indeed, evidence exists for interactions between pancreatic cancer cells and stromal fibroblasts that affect the invasive phenotype of pancreatic cancer (Maehara et al., 2001). In contrast to the substantial progress in our understanding of the genetic and epigenetic events that occur within pancreatic cancer cells, molecular mechanisms associated with the tumor-host interactions have not been well characterized. Ryu and colleagues used serial analysis of gene expression (SAGE) to compare gene expression profiles of primary carcinomas and passaged cancer cell lines, and identified a cluster of invasion-specific genes (Ryu et al., 2001). Many of the genes identified were expressed specifically by stromal cells adjacent to the neoplastic epithelium, thus representing potential mediators of the tumor-host interactions (Iacobuzio-Donahue et al., 2002b).
SPARC (secreted protein acidic and rich in cysteine)/osteonectin/BM 40 is a matricellular glycoprotein involved in diverse biological processes, including tissue remodeling, wound repair, morphogenesis, cellular differentiation, cell proliferation; cell migration, and angiogenesis (Jendraschak and Sage, 1996; Yan and Sage, 1999; Bradshaw and Sage, 2001; Brekken and Sage, 2001). SPARC is highly expressed in a wide range of human malignant neoplasms, and the deregulated expression of SPARC is often correlated with disease progression and/or poor prognosis (Wewer et al., 1988; Bellahcene and Castronovo, 1995; Porte et al., 1995; Porter et al., 1995; Ledda et al., 1997; Porte et al., 1998; Massi et al., 1999; Rempel et al., 1999; Thomas et al., 2000; Yamanaka et al., 2001). Interestingly, in certain tumor types, strong expression of SPARC has been detected predominantly in the stroma adjacent to the neoplastic cells (Le Bail et al., 1999; Paley et al., 2000; Iacobuzio-Donahue et al., 2002a). These findings have led to the hypothesis that SPARC plays a role in tumor progression at the site of interface between neoplastic cells and the surrounding host cells. Recently, Yiu and coworkers have shown that treatment of ovarian cancer cells with exogenous SPARC inhibits cell proliferation and induces apoptosis (Yiu et al., 2001). In addition, forced expression of SPARC in ovarian cancer cells resulted in reduced tumorigenicity in nude mice, suggesting that SPARC has a tumor-suppressor function (Mok et al., 1996). In addition to its effects on cellular proliferation, SPARC has been linked with tumor invasion. SPARC has been shown to increase the invasive capacity of prostate and breast cancer cells in vitro (Jacob et al., 1999; Briggs et al., 2002) and promote invasion of glioma in vivo (Schultz et al., 2002). Thus, the biological functions of SPARC appear to be variable among cancer types, and it is not known whether this protein is involved in pancreatic cancer progression.
There is an urgent need, therefore, to determine SPARC's exact role in pancreatic cancer and other types of cancer. Furthermore, there is also a great need for the development of new methods for detection and diagnosis of pancreatic cancers, particularly at a pre-invasive or early stage of the disease so that early medical intervention can be more effective at saving lives. Indeed, new methods of detection for pancreatic cancer may be useful in diagnosing other types of cancer, as well.